Summary High-density lipoprotein (HDL) is key a component of circulating blood and plays essential roles in vascular endothelial cells and immunity. However, the levels of HDL decrease by 40-70% in septic patients, which is associated with a poor prognosis. Using ApoAI null mice as an HDL deficient model, we recently reported that mice lacking HDL are susceptible to cecal ligation and puncture (CLP)-induced septic death, and increase HDL levels by over expression of ApoAI protects CLP-induced septic death. These clinical and animal studies indicate that a decrease in HDL levels is a risk factor for sepsis and raising circulating HDL levels may provide an efficient therapy for sepsis. In the preliminary study, we demonstrated that synthetic HDL (sHDL) treatment significantly protects mice from CLP-induced septic death, indicating that sHDL is a potential effective therapy for sepsis. We hypothesize that sHDL therapy protects sepsis by restoring both HDL level and its immune- and vascular-protective functions. The objectives of this grant are to understand the mechanism(s) underlying sHDL vascular protection, to use this information to tailor the sHDL composition and to optimize treatment strategy specifically for sepsis. To achieve the grant objectives we plan to: 1) determine the mechanisms of sHDL's protection against sepsis-induced vascular pathogenesis; 2) Tailor sHDL composition for increased efficacy in sepsis; and 3) Optimize the sHDL treatment regimen for sepsis and test in immunocompromised septic mice. Completion of this preclinical study will provide a body of mechanistic data for a novel sHDL-based therapeutic approach for treatment of sepsis and position it for rapid clinical translation.